CN1569882A - Process for preparing protopanoxadiol and protopanaxatriol - Google Patents
Process for preparing protopanoxadiol and protopanaxatriol Download PDFInfo
- Publication number
- CN1569882A CN1569882A CN 200410018038 CN200410018038A CN1569882A CN 1569882 A CN1569882 A CN 1569882A CN 200410018038 CN200410018038 CN 200410018038 CN 200410018038 A CN200410018038 A CN 200410018038A CN 1569882 A CN1569882 A CN 1569882A
- Authority
- CN
- China
- Prior art keywords
- protopanoxadiol
- protopanaxatriol
- preparation
- reaction
- alkaline hydrolysis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SHCBCKBYTHZQGZ-DLHMIPLTSA-N protopanaxatriol Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2[C@@H](O)C[C@@]3(C)[C@]4(C)CC[C@H]([C@](C)(O)CCC=C(C)C)[C@H]4[C@H](O)C[C@@H]3[C@]21C SHCBCKBYTHZQGZ-DLHMIPLTSA-N 0.000 title claims abstract description 41
- BBEUDPAEKGPXDG-UHFFFAOYSA-N protopanaxatriol Natural products CC(CCC=C(C)C)C1CCC2(C)C1C(O)CC3C4(C)CCC(O)C(C)(C)C4C(O)CC23C BBEUDPAEKGPXDG-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 229930182490 saponin Natural products 0.000 claims abstract description 50
- 150000007949 saponins Chemical class 0.000 claims abstract description 45
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims abstract description 31
- 239000000284 extract Substances 0.000 claims abstract description 20
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000004440 column chromatography Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- -1 sodium alkoxide Chemical class 0.000 claims description 12
- 241000208343 Panax Species 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 241001065361 Gynostemma Species 0.000 claims description 4
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims 1
- 240000006509 Gynostemma pentaphyllum Species 0.000 abstract description 8
- 235000002956 Gynostemma pentaphyllum Nutrition 0.000 abstract description 6
- 240000004371 Panax ginseng Species 0.000 abstract 1
- 235000017709 saponins Nutrition 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 241000196324 Embryophyta Species 0.000 description 14
- 229930182494 ginsenoside Natural products 0.000 description 13
- 229940089161 ginsenoside Drugs 0.000 description 13
- 244000131316 Panax pseudoginseng Species 0.000 description 11
- 238000003810 ethyl acetate extraction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000010828 elution Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 241000168720 Panax japonicus Species 0.000 description 6
- 235000003140 Panax quinquefolius Nutrition 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 description 5
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 description 5
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 description 5
- 235000003181 Panax pseudoginseng Nutrition 0.000 description 5
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 5
- 235000008434 ginseng Nutrition 0.000 description 5
- 229940100243 oleanolic acid Drugs 0.000 description 5
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 description 5
- 241000180649 Panax notoginseng Species 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 241000208340 Araliaceae Species 0.000 description 3
- 235000003143 Panax notoginseng Nutrition 0.000 description 3
- 244000138620 Talinum patens Species 0.000 description 3
- 235000004083 Talinum patens Nutrition 0.000 description 3
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 235000005769 Japanese ginseng Nutrition 0.000 description 2
- 235000002791 Panax Nutrition 0.000 description 2
- 235000002789 Panax ginseng Nutrition 0.000 description 2
- 235000003174 Panax japonicus Nutrition 0.000 description 2
- 241000620166 Panax pseudoginseng subsp. himalaicus Species 0.000 description 2
- 241000168719 Panax zingiberensis Species 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000002481 ethanol extraction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- TXEWRVNOAJOINC-UHFFFAOYSA-N ginsenoside Rb2 Natural products CC(=CCCC(OC1OC(COC2OCC(O)C(O)C2O)C(O)C(O)C1O)C3CCC4(C)C3C(O)CC5C6(C)CCC(OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C(C)(C)C6CCC45C)C TXEWRVNOAJOINC-UHFFFAOYSA-N 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 240000008027 Akebia quinata Species 0.000 description 1
- 235000007756 Akebia quinata Nutrition 0.000 description 1
- 241000219104 Cucurbitaceae Species 0.000 description 1
- UFNDONGOJKNAES-UHFFFAOYSA-N Ginsenoside Rb1 Natural products CC(=CCCC(C)(OC1OC(COC2OC(CO)C(O)C(O)C2O)C(O)C(O)C1O)C3CCC4(C)C3C(O)CC5C6(C)CCC(OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C(C)(C)C6CC(O)C45C)C UFNDONGOJKNAES-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 241000168721 Panax stipuleanatus Species 0.000 description 1
- 241001527087 Panax vietnamensis Species 0.000 description 1
- 235000003176 Panax zingiberensis Nutrition 0.000 description 1
- YQKCHRBAJSATCG-UHFFFAOYSA-N UNPD30744 Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC(C)(CCC=C(C)C)C2C3C(C4(CCC5C(C)(C)C(OC6C(C(O)C(O)C(CO)O6)OC6C(C(O)C(O)C(CO)O6)O)CCC5(C)C4CC3O)C)(C)CC2)O1 YQKCHRBAJSATCG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- BDFJWKALVSRGSR-UHFFFAOYSA-N butan-1-ol;sodium Chemical compound [Na].CCCCO BDFJWKALVSRGSR-UHFFFAOYSA-N 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- GZYPWOGIYAIIPV-JBDTYSNRSA-N ginsenoside Rb1 Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(CC[C@H]4C(C)(C)[C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GZYPWOGIYAIIPV-JBDTYSNRSA-N 0.000 description 1
- NODILNFGTFIURN-USYOXQFSSA-N ginsenoside Rb3 Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(CC[C@H]4C(C)(C)[C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)O[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O NODILNFGTFIURN-USYOXQFSSA-N 0.000 description 1
- PFSIGTQOILYIIU-UHFFFAOYSA-N ginsenoside Rb3 Natural products CC(=CCCC(C)(O)C1CCC2(C)C3CCC4C(C)(C)C(CCC4(C)C3CC(OC5OC(COC6OCC(O)C(O)C6O)C(O)C(O)C5O)C12C)OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C PFSIGTQOILYIIU-UHFFFAOYSA-N 0.000 description 1
- UVBLDLGZDSGCSN-UHFFFAOYSA-N ginsenoside-Rb3 Natural products C1=CC2C3(C)CCC(O)C(C)(C)C3CCC2(C)C2(C)CCC34CCC(C)C(C)C4C21OC3=O UVBLDLGZDSGCSN-UHFFFAOYSA-N 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- IUCHKMAZAWJNBJ-RCYXVVTDSA-N oleanolic acid 3-O-beta-D-glucosiduronic acid Chemical compound O([C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@]1(CCC(C[C@H]14)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O IUCHKMAZAWJNBJ-RCYXVVTDSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical group N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention relates to the process for preparing protopanoxadiol and protopanaxatriol by using general saponin extract from panax ginseng plant leaves and gynostemma pentaphylla extractive as raw material for alkaline hydrolysis reaction in organic solvent through column chromatography and purification.
Description
Technical field
The present invention relates to protopanoxadiol and Protopanaxatriol's preparation method, specifically be about being raw material, by oxidation alkaline hydrolysis prepared in reaction protopanoxadiol and Protopanaxatriol's method with the panax species that contains ginsenoside or the total saponin extracts of leaf, the Herb Gynostemmae Pentaphylli extract of gynostemma plant.
Background technology
Araliaceae (Araliaceae) Panax (Panax) plant has very high pharmaceutical use, its main effective constituent is saponin component, can roughly be divided into three major types by aglycon structure difference: protopanoxadiol saponins (Protopanaxdiol-type Gisenosides), Protopanaxatriol's saponins (Protopanaxtriol-type Gisnosides) and Oleanolic Acid saponins.This genus medicinal plant has following: first kind plant, saponin component have protopanoxadiol saponins and Protopanaxatriol's saponins, and such plant has pseudo-ginseng (P.notoginseng) (total saponin content 8-12%), three leaf gensengs (P.trifolious); The second class plant, saponin component is based on protopanoxadiol saponins and Protopanaxatriol's saponins, but also contain a small amount of Oleanolic Acid saponins, genseng (Radix Ginseng) (total saponin content 2.0-3.5%), Radix Panacis Quinquefolii (Panaxquinquefolium L.) (total saponin content 6.4-7.3%) are the representative of this plant; In the 3rd class plant, content, the kind of protopanoxadiol saponins, Protopanaxatriol's saponins and Oleanolic Acid saponins are suitable in the saponin component, as: Vietnam's genseng (P.vietnamensis), Himalaya panicled fameflower root (P.pseudo-ginseng subsp.Himalaicus), rhizome of Japanese Ginseng (P.japonicus), Rhizoma Panacis bipinnatifidi (P.japonicus var bipinnatifolius), Rhizome of Bipinnatifid Ginseng (P.japonicus var major), narrow leaf rhizome of Japanese Ginseng (P.japonicus var angustifolius).In the 4th class plant, saponin component is based on the Oleanolic Acid saponins, as: narrow leaf panicled fameflower root (P.pseudo-ginseng subsp.himalaicus var angustifolius), panicled fameflower root (P.pseudo-ginseng WALL subsp.pseudo-ginseng), Panax zingiberensis C. Y. Wu. Et Feng (P.zingiberensis), Pinpien Ginseng (P.stipuleanatus).
Though and gynostemma pentaphylla belongs to Curcurbitaceae (Cucurbitaceae) gynostemma pentaphyllum genus (Gynostemma B1) plant, but more than the 50 kind of genseng saponin constituent that it contains, function with similar genseng, wherein Rhizome or herb of Fiveleaf Gynostemma saponin I II, IV, VII, XII are four kinds, are same substances with ginsenoside Rb1, Rb3, Rd, F2 respectively; Its acid hydrolysis products and ginsenoside acid hydrolysis products---panoxadiol has identical physico-chemical property, this is very rare in the plant of non-Araliaceae, thereby is described as " second genseng ".
About protopanoxadiol and Protopanaxatriol's preparation method, bibliographical information has:
(1) the ginsenoside acid hydrolysis prepares protopanoxadiol (Chinese patent: CN1417224A, 2003)
Ginsenoside is dissolved in contains in protectant organic solvent acidic aqueous solution hydrolysis 7-10 days.
Though this method has been alleviated ginsenoside unstable destructible under acidolysis condition, the problem of easy cyclisation, but this method require raw materials used ginsenoside purity necessary 〉=90%, and can not contain triol type saponin(e in the diol type saponin(e, promptly this method will be carried out separating of diol type saponin(e and triol type saponin(e to crude extract, feed purification is had relatively high expectations, and reaction yield is not high.
(2) high temperature alkaline hydrolysis method (Chinese patent: CN1122042C, 2003)
Ginsenoside is dissolved in the solution of alkali metal hydroxide and high boiling point aliphatic alcohols organism composition, heating is hydrolyzed, and can obtain protopanoxadiol and Protopanaxatriol's monomer through methods such as silica gel column chromatography, ODS column chromatography, recrystallization or HPLC.
This method need at high temperature be carried out, and obtain after the hydrolysis also mostly be to mix saponin, so target product protopanoxadiol and Protopanaxatriol's monomeric yield is not high.
Summary of the invention
For this reason, the object of the present invention is to provide a kind of protopanoxadiol and Protopanaxatriol's preparation method.This method has the reaction conditions gentleness, and cost is low, the characteristics of the easily separated purifying of product, can high yield obtain highly purified protopanoxadiol and Protopanaxatriol, be the method that is fit to suitability for industrialized production.
Method of the present invention can be represented with following reaction formula:
A1 A2 (protopanoxadiol) A3 (Protopanaxatriol)
A kind of panoxadiol of the present invention and Protopanaxatriol's preparation method, this method is that the total saponin extract with panax species that contains ginsenoside or leaf, the Herb Gynostemmae Pentaphylli extract of gynostemma plant are raw material, in organic solvent, carry out the reaction of oxidation alkaline hydrolysis, through column chromatography purification, can high yield obtain highly purified protopanoxadiol and Protopanaxatriol.
Panax species in the raw material sources, we preferably use first kind plant, it is the plant that saponin component only contains protopanoxadiol saponins and Protopanaxatriol's saponins, and the second class plant, be saponin component based on protopanoxadiol saponins and Protopanaxatriol's saponins, but also contain the plant of a small amount of Oleanolic Acid saponins, simultaneously, panax species leaf glucoside mainly is made up of the protopanoxadiol saponin(e, has only Protopanaxatriol's saponin(e seldom.Total saponin extract of panax species or leaf both can oneself be prepared by us, also can directly buy from producer, and the Herb Gynostemmae Pentaphylli extract of gynostemma plant is bought from producer.
In reaction, total saponin extract of panax species or leaf, the Herb Gynostemmae Pentaphylli extract of gynostemma plant and organic solvent amount ratio be 40-120g/L;
Organic solvent is C
2-C
10Saturated monohydroxy alcohol, ethylene glycol, propylene glycol, 1,3 butylene glycol, 1, the mixture of one or more in 4-butyleneglycol, the glycerol;
Carry out alkaline hydrolysis with sodium alkoxide, sodium alkoxide is to be selected from C
1-C
6Sodium alkoxide in a kind of, concentration range is 0.2～1.5mol/L;
The alkaline hydrolysis temperature is 80-140 ℃, and the reaction times is 24-90 hour;
Oxidation is meant and continues aerating oxygen or pressurized air in reaction.
The used leacheate of column chromatography purification is two or more a mixture in methyl alcohol, chloroform, sherwood oil, ethyl acetate, methylene dichloride or the hexanaphthene.
The inventive method prepares the protopanoxadiol method with respect to the ginsenoside acid hydrolysis, neither there is the unstable destructible of ginsenoside, the problem of easy cyclisation, do not need raw materials used extract is carried out separating of diol type saponin(e and triol type saponin(e yet, then the requirement of phase intercommunication feed purification is just not high, but the easily separated purifying of target product; And with respect to high temperature alkaline hydrolysis method, reaction conditions gentleness of the present invention, and the easily separated purifying of target product, can high yield obtain highly purified protopanoxadiol and Protopanaxatriol, so use the inventive method can be simply, convenient, low cost, industrialization prepare protopanoxadiol and Protopanaxatriol in a large number, antitumor to satisfy, resist requirement of providing medicinal such as cardiovascular.
Embodiment
Below, can further understand the present invention, but can not limit content of the present invention by specific embodiment.
Embodiment 1
Pseudo-ginseng 18kg (specification: countless heads, available from Yunnan) be ground into Powdered (100-200 order), use 30kg 95% alcohol immersion two days, filter, filtrate concentrate the pseudo-ginseng ethanol extraction, ethanol reclaim to reuse soaks filter residue six times, final accumulative total pseudo-ginseng ethanol extraction 3.37kg, it is soluble in water, with Petroleum ether extraction three times, water intaking is used n-butanol extraction four times mutually, and n-butanol layer concentrates, altogether Radix Notoginseng total arasaponins n-butanol extract 1.78kg.
Get total saponin extracts 100g and be dissolved in the 1300ml propyl carbinol, heating is stirred, and (chemical pure, purity: 80%) (1.56mol, concentration: 1.2mol/L), lead to oxygen, 90 ℃ were reacted 65 hours 132.6g, and reaction finishes to add sodium ethylate.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, n-butanol layer concentrates the back and uses water dissolution, ethyl acetate extraction, and ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [1～5% methanol gradient elution] purifying, get protopanoxadiol (A2) 6g, it is 97.93% that HPLC measures purity; Protopanaxatriol (A3) 11g, it is 99.95% that HPLC measures purity.The materialization data that compound (A3) is measured are coincident with literature value: Chen Yingjie et al, Journal of ShenyangCollege of Pharmacy, 1987,4 (4), 282-289.
The materialization data that compound (A3) is measured are as follows:
1H?NMR(300MHz，CDCl
3)：δ5.18(d，1H)，4.14(m，1H)，3.6(m，1H)，3.2(s，1H)，2.15-1.61(m，20H)，1.58-1.17(m，12H)，1.05(s，5H)，1.01(s，3H)，0.95(d，8H)。
13C?NMR(300MHz，CDCl
3)：132.1，125.2，78.8，74.7，71.0，68.9，61.4，53.7，51.7，49.8，47.7，47.2，41.2，39.6，39.4，39.1，34.8，31.4，31.3，31.2，27.3，27.2，26.7，26.0，22.6，18.0，17.5，17.4，17.1，15.8。
Embodiment 2
Get extract of panax notoginseng saponins 100g (preparing among the embodiment 1) and be dissolved in the 1500ml Pentyl alcohol, heating is stirred, add propyl carbinol sodium (chemical pure, purity: 150g (1.56mol, concentration: 1.04mol/L) 80%), logical pressurized air, 100 ℃ were reacted 60 hours, and reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, n-butanol layer concentrates the back and uses water dissolution, ethyl acetate extraction, and ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [hexanaphthene: ethyl acetate=10: 1-1: 1 (V/V) gradient elution] purifying, get protopanoxadiol (A2) 8g, it is 97% that HPLC measures purity; Protopanaxatriol (A3) 15g, it is 99% that HPLC measures purity.The materialization data that compound (A3) is measured are coincident with literature value: Chen Yingjie et al, Journal of Shenyang College of Pharmacy, 1987,4 (4), 282-289.
Embodiment 3
Folium Notoginseng glycoside (content: in ginsenoside Rb3,91.9%; Available from Yunnan) 1000g is dissolved in the 14L propyl carbinol, heating is stirred, add sodium ethylate (chemical pure, purity: 80%) 1190g (14.0mol, concentration: 1.0mol/L), logical oxygen, 110 ℃ of reactions 55 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, n-butanol layer concentrates and uses water dissolution, ethyl acetate extraction, and ethyl acetate extraction is through washing, dry, evaporate to dryness.Through silica gel column chromatography [sherwood oil: ethyl acetate=9: 1-2: 1 (V/V) gradient elution] purifying, get protopanoxadiol (A2) 181.6g, it is 99.3% that HPLC measures purity.Its materialization data are coincident with literature value: J.Asakawa et al, Tetrahedron, 1977,33,1935-939; Nagai, M.etal, Chem.Pharm.Bull, 1972,20 (6), 1212-1216.
The materialization data that compound (A2) is measured are as follows:
1H?NMR(300MHz，CDCl
3)：δ5.13(t，1H)，3.6(m，1H)，3.2(s，1H)，2.15-1.72(m，12H)，1.64-1.22(m，14H)，1.01(d，8H)，0.92(s，6H)，0.81(s，6H)，0.78(s，3H)。
13C?NMR(300MHz，CDCl
3)：131.4，125.2，78.8，74.0，70.8，56.0，53.6，51.6，50.2，47.7，39.8，39.0，39.0，37.1，34.8，34.8，31.2，31.1，28.1，27.4，26.8，26.6，25.8，22.4，18.3，17.8，16.9，16.2，15.7，15.5。
Embodiment 4
Folium Notoginseng glycoside (content: in ginsenoside Rb3 greater than 85%; Available from Yunnan) 1000g is dissolved in 10L propyl carbinol and the 4L isopropylcarbinol mixed solvent, heating is stirred, add sodium ethylate (chemical pure, purity: 80%) 1230g (14.5mol, concentration: 1.04mol/L), logical pressurized air, 90 ℃ of reactions 88 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, n-butanol layer concentrates the back and uses water dissolution, ethyl acetate extraction, and ethyl acetate extraction is through washing, dry, evaporate to dryness.Through silica gel column chromatography [sherwood oil: ethyl acetate=8: 1-2: 1 (V/V) gradient elution] purifying, get protopanoxadiol (A2) 157.0g, it is 97.9% that HPLC measures purity.The materialization data of its mensuration and conforming to of embodiment 3 products.
Embodiment 5
Red ginseng (total saponin content 2.36%; Available from Anhui) extract 5g is dissolved in 100ml 1, in the 4-butyleneglycol, stirs, add sodium tert-butoxide (chemical pure, purity: 97%) 3.96g (0.04mol, concentration: 0.4mol/L), logical oxygen, 130 ℃ of reactions 41 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, n-butanol layer concentrates the back and uses water dissolution, ethyl acetate extraction, and ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [1～8% methanol/dichloromethane solution gradient elution] purifying, get protopanoxadiol (A2) 150mg, HPLC measures purity＞98%; Protopanaxatriol (A3) 90mg, HPLC measures purity＞98%.The materialization data that they are measured conform to embodiment 1,3 products.
Embodiment 6
Red ginseng (total saponin content 2.36%; Available from Anhui) extract 5g is dissolved in the 80ml glycerol, stirs, add sodium propylate (chemical pure) 3.28g (0.04mol, concentration: 0.5mol/L), feed pressurized air, 135 ℃ of reactions 36 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, n-butanol layer concentrates the back and uses water dissolution, ethyl acetate extraction, and ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [hexanaphthene: ethyl acetate=10: 1-3: 1 (V/V) gradient elution] purifying, get protopanoxadiol (A2) 136mg, it is＞98% that HPLC measures purity; Protopanaxatriol (A3) 92mg, it is＞98% that HPLC measures purity.The materialization data that they are measured conform to embodiment 1,3 products.
Embodiment 7
Stem and leaf of Radix Panacis Quinquefolii extrac (Radix Ginseng total saponins content 85%; Available from Jilin) 10g is dissolved in the 100ml n-hexyl alcohol, heating is stirred, add sodium methylate (chemical pure, purity: 50%) 12.96g (0.12mol, concentration: 1.2mol/L), logical oxygen, 120 ℃ of reactions 70 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, ethyl acetate extraction, ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [1～5% methanol gradient elution] purifying, get protopanoxadiol (A2) 650mg, HPLC measures purity＞98%; Protopanaxatriol (A3) 450mg, HPLC measures purity＞98%.The materialization data that they are measured conform to embodiment 1,3 products.
Embodiment 8
Radix Panacis Quinquefolii root extract (Radix Ginseng total saponins content 30%; Available from Jilin) 10g is dissolved in the 100ml ethylene glycol, heating is stirred, add sodium methylate (chemical pure, purity: 50%) 12.96g (0.12mol, concentration: 1.2mol/L), logical oxygen, 130 ℃ of reactions 55 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, ethyl acetate extraction, ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [sherwood oil: ethyl acetate=9: 1-2: 1 (V/V) gradient elution] purifying, get protopanoxadiol (A2) 300mg, HPLC measures purity＞98%; Protopanaxatriol (A3) 250mg, HPLC measures purity＞98%.The materialization data that they are measured conform to embodiment 1,3 products.
Embodiment 9
(total saponin content is about 80%, wherein ginsenoside Rb for gynostemma pentaphylla
1Account for 6%, former ginsenoside Rg accounts for 20%; Available from Hubei) extract 10g is dissolved in the 100ml ethanol, heating is stirred, add sodium ethylate (chemical pure, purity: 80%) 10.2g (0.12mol, concentration: 1.2mol/L), logical oxygen, 80 ℃ of reactions 84 hours, reaction finishes.Reaction solution is chilled to room temperature, and with the saturated washing of propyl carbinol, ethyl acetate extraction, ethyl acetate layer washes with water, drying.After concentrating, through silica gel column chromatography [sherwood oil: ethyl acetate=10: 1-2: 1 (V/V) gradient elution] purifying, get protopanoxadiol (A2) 450mg, HPLC measures purity＞98%; Protopanaxatriol (A3) 950mg, HPLC measures purity＞98%.The materialization data that they are measured conform to embodiment 1,3 products.
Claims (5)
1, a kind of protopanoxadiol and Protopanaxatriol's preparation method, it is characterized in that the total saponin extracts with panax species or leaf, the Herb Gynostemmae Pentaphylli extract of gynostemma plant are raw material, in organic solvent, carry out the reaction of oxidation alkaline hydrolysis, through column chromatography purification, make protopanoxadiol and Protopanaxatriol: wherein:
The amount ratio of the total saponin extracts of panax species or leaf, the Herb Gynostemmae Pentaphylli extract of gynostemma plant and organic solvent is 40-120g/L, carry out alkaline hydrolysis with sodium alkoxide, concentration range is 0.2-1.5mol/L, and the alkaline hydrolysis temperature is 80-140 ℃, and the reaction times is 24-90 hour.
2, preparation method as claimed in claim 1 is characterized in that described organic solvent is C
2-C
10Saturated monohydroxy alcohol, ethylene glycol, propylene glycol, 1,3 butylene glycol, 1,4-butyleneglycol, the mixture of one or more in the glycerol.
3, preparation method as claimed in claim 1 is characterized in that the sodium alkoxide of using in the described alkaline hydrolysis reaction is to be selected from C
1-C
6A kind of in the sodium alkoxide.
4, preparation method as claimed in claim 1 is characterized in that described oxidation is to continue aerating oxygen or pressurized air in reaction.
5, preparation method as claimed in claim 1 is characterized in that the used leacheate of described column chromatography purification is two or more a mixture in methyl alcohol, chloroform, sherwood oil, ethanol ethyl ester, methylene dichloride or the hexanaphthene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410018038 CN1252082C (en) | 2004-04-29 | 2004-04-29 | Process for preparing protopanoxadiol and protopanaxatriol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410018038 CN1252082C (en) | 2004-04-29 | 2004-04-29 | Process for preparing protopanoxadiol and protopanaxatriol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1569882A true CN1569882A (en) | 2005-01-26 |
| CN1252082C CN1252082C (en) | 2006-04-19 |
Family
ID=34479315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410018038 Expired - Lifetime CN1252082C (en) | 2004-04-29 | 2004-04-29 | Process for preparing protopanoxadiol and protopanaxatriol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1252082C (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101508965B (en) * | 2008-10-27 | 2011-08-03 | 昆明诺唯金参生物工程有限责任公司 | Process of preparing 20(S)-ginsenoside Rh1 with streptomycete fermentation of pseudo-ginseng saponin |
| CN102311474A (en) * | 2010-07-07 | 2012-01-11 | 北京师范大学 | Method for preparing protopanaxadiol and protopanaxatriol by solvent-free method |
| US8148354B2 (en) | 2006-06-09 | 2012-04-03 | Shanghai Innovative Research Center Of Traditional Chinese Medicine | Use of 20(S)-protopanaxadiol in manufacture of antidepressants |
| CN102558271A (en) * | 2012-01-16 | 2012-07-11 | 沈阳药科大学 | Industrial preparation method of pseudoginsenoside |
| CN103961358A (en) * | 2013-01-31 | 2014-08-06 | 上海中药创新研究中心 | Application of protopanaxadiol derivative and protopanaxatriol derivative in preparation of drugs |
| WO2017117903A1 (en) * | 2016-01-08 | 2017-07-13 | 赵树民 | Method for preparing 20(s)-protopanaxadiol |
| CN108558976A (en) * | 2018-04-13 | 2018-09-21 | 深圳以诺生物制药有限公司 | The preparation method of low polarity rare ginsenoside Δ PPD and Δ PPT |
| CN113214338A (en) * | 2021-05-21 | 2021-08-06 | 吉林大学 | Crystal and single crystal of protopanaxatriol and preparation method thereof |
| CN113637044A (en) * | 2021-05-08 | 2021-11-12 | 中国人民解放军海军军医大学 | Method for efficiently and rapidly preparing protopanaxadiol and protopanaxatriol |
| CN114702541A (en) * | 2022-01-23 | 2022-07-05 | 吉林农业大学 | Novel large-scale preparation method of compound 20(S) -protopanaxatriol PPT |
-
2004
- 2004-04-29 CN CN 200410018038 patent/CN1252082C/en not_active Expired - Lifetime
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8148354B2 (en) | 2006-06-09 | 2012-04-03 | Shanghai Innovative Research Center Of Traditional Chinese Medicine | Use of 20(S)-protopanaxadiol in manufacture of antidepressants |
| CN101508965B (en) * | 2008-10-27 | 2011-08-03 | 昆明诺唯金参生物工程有限责任公司 | Process of preparing 20(S)-ginsenoside Rh1 with streptomycete fermentation of pseudo-ginseng saponin |
| CN102311474B (en) * | 2010-07-07 | 2016-02-24 | 北京师范大学 | Application solventless method prepares protopanoxadiol and Protopanaxatriol |
| CN102311474A (en) * | 2010-07-07 | 2012-01-11 | 北京师范大学 | Method for preparing protopanaxadiol and protopanaxatriol by solvent-free method |
| CN102558271A (en) * | 2012-01-16 | 2012-07-11 | 沈阳药科大学 | Industrial preparation method of pseudoginsenoside |
| CN103961358B (en) * | 2013-01-31 | 2016-07-06 | 上海中药创新研究中心 | Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant |
| CN103961358A (en) * | 2013-01-31 | 2014-08-06 | 上海中药创新研究中心 | Application of protopanaxadiol derivative and protopanaxatriol derivative in preparation of drugs |
| WO2017117903A1 (en) * | 2016-01-08 | 2017-07-13 | 赵树民 | Method for preparing 20(s)-protopanaxadiol |
| CN106957351A (en) * | 2016-01-08 | 2017-07-18 | 杨丽娟 | The preparation method of 20 (S)-protopanoxadiols |
| CN108558976A (en) * | 2018-04-13 | 2018-09-21 | 深圳以诺生物制药有限公司 | The preparation method of low polarity rare ginsenoside Δ PPD and Δ PPT |
| CN113637044A (en) * | 2021-05-08 | 2021-11-12 | 中国人民解放军海军军医大学 | Method for efficiently and rapidly preparing protopanaxadiol and protopanaxatriol |
| CN113637044B (en) * | 2021-05-08 | 2023-11-03 | 中国人民解放军海军军医大学 | Method for preparing protopanoxadiol and protopanaxatriol |
| CN113214338A (en) * | 2021-05-21 | 2021-08-06 | 吉林大学 | Crystal and single crystal of protopanaxatriol and preparation method thereof |
| CN114702541A (en) * | 2022-01-23 | 2022-07-05 | 吉林农业大学 | Novel large-scale preparation method of compound 20(S) -protopanaxatriol PPT |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1252082C (en) | 2006-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1252082C (en) | Process for preparing protopanoxadiol and protopanaxatriol | |
| CN101736050B (en) | Preparation method of arctigenin | |
| CN100396783C (en) | Chinese starjasmine stem lignin aglycone total extract and its extracting process | |
| CN105585471A (en) | Extraction method of active ingredients of isodon amethystoides | |
| CN100537594C (en) | Method for preparing purity astragaloside | |
| CN102093453B (en) | Method for preparing 20(R)-25-hydroxy-dammarane type-3beta,12beta,20-triols | |
| CN1091448C (en) | Method for preparing 20(S)-ginsenoside-RH2, medicinal compositions therewith and use thereof | |
| CN101205249B (en) | Method for preparing laxogenin by smilax scobinicaulis plants | |
| CN1765917A (en) | Gen-seng saponin Rb2 preparation process | |
| CN1189176C (en) | Astragalus root methyl-glycoside composition and preparation method | |
| CN101613384B (en) | Dihydroxyphenethyl alcohol glycoside compound and preparation method thereof | |
| CN106928307A (en) | Triterpene compound and preparation method thereof in birch stripping pipe bacterium | |
| CN102775461A (en) | Method for preparing 20 (R)-ginseniside Rg3 | |
| CN102603833B (en) | Extraction and separation process of apigenin-7-O-beta-D-glucopyranside from garden balsam stem | |
| CN108129541B (en) | Triterpenoid extracted from Ganoderma, and its preparation method and application | |
| CN1186345C (en) | Method of extracting peucedanin from angelica | |
| CN102050787B (en) | Guanidine derivatives and preparation, medicinal composition and application in preparation of medicaments for treating metabolic syndromes | |
| CN101817828B (en) | Preparation of bergenin in aruneus dioicus | |
| CN101429225B (en) | Method for producing asiatic acid with asiaticoside acid hydrolysis | |
| CN109438548B (en) | Preparation method of paris polyphylla pennogenin Pb | |
| CN102286064B (en) | Compound with insulin-sensitizing activity as well as preparation method and application thereof | |
| CN111217800A (en) | Alkaloid, and extraction method and application from black pepper | |
| CN102977177B (en) | Triterpenoid saponin class anti-myocardial ischemia chemical compound extracted from clematis tangutica | |
| CN115521322B (en) | Isopentenyl flavone compound, and preparation method and application thereof | |
| CN112194690B (en) | 3 compounds in radix Rubiae and extraction and separation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: WUXI ZHONGHUI CHINESE MEDICINE CO., LTD. Free format text: FORMER OWNER: CHUANGXIN CHINESE MEDICINE RESEARCH CENTER, SHANGHAI Effective date: 20101223 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 201203 BUILDING 1, NO.439, CHUNXIAO ROAD, HIGH TECHNOLOGY PARK, ZHANGJIANG, PUDONG NEW DISTRICT, SHANGHAI TO: 214101 NO.99, FURONG MIDDLE ROAD 3, ECONOMIC DEVELOPMENT ZONE, XISHAN, WUXI CITY, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20101223 Address after: 214101 No. three, No. 99, Furong Road, Xishan Economic Development Zone, Jiangsu, Wuxi Patentee after: Wuxi Zhonghui Medicine Co.,Ltd. Address before: 201203 Shanghai Zhangjiang High Tech Park of Pudong New Area Chunxiao Road No. 439 Building No. 1 Patentee before: SHANG HAI INNOVATIVE RESEARCH CENTER OF TRADITIONAL CHINESE MEDICINE. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20200729 Address after: Room 310, 3rd floor, town living room, No. 999, Gaoxin East Road, Xinxiang City, Henan Province Patentee after: Xinxiang yiruida Pharmaceutical Technology Co.,Ltd. Address before: 214101 No. three, No. 99, Furong Road, Xishan Economic Development Zone, Jiangsu, Wuxi Patentee before: Wuxi Zhonghui Medicine Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221017 Address after: 214192 99 Xishan road three, Xishan Economic Development Zone, Wuxi, Jiangsu Patentee after: Wuxi Zhonghui Medicine Co.,Ltd. Address before: Room 310, 3rd floor, small town living room, 999 Gaoxin East Road, Xinxiang City, Henan Province Patentee before: Xinxiang yiruida Pharmaceutical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221219 Address after: Room 118, building 20, no.1-42, Lane 83, Hongxiang North Road, Lingang New District, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 2013 13 Patentee after: Yiruida (Shanghai) Pharmaceutical Technology Co.,Ltd. Address before: 214192 99 Xishan road three, Xishan Economic Development Zone, Wuxi, Jiangsu Patentee before: Wuxi Zhonghui Medicine Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CX01 | Expiry of patent term |
Granted publication date: 20060419 |